Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes

Abstract

The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine if their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA was repressed 49–72% by 1,25D in primary human and CCD-1106 KERTr keratinocytes; a functional vitamin D responsive element (VDRE) was identified at −9590 bp in murine Soggy. Similarly, SOSTDC1 mRNA was repressed 41–59% by 1,25D in KERTr and primary human keratinocytes; a functional VDRE was located at −6215 bp in human Wise. In contrast, HR mRNA was upregulated 1.56–2.77-fold by 1,25D in primary human and KERTr keratinocytes; a VDRE (TGGTGAgtgAGGACA) consisting of an imperfect direct repeat separated by 3 nucleotides (DR3) was identified at −7269 bp in the human Hairless gene that mediated dramatic induction, even in the absence of 1,25D ligand. In parallel, a DR4 thyroid hormone responsive element, TGGTGAggccAGGACA, was identified at +1304 bp in the human HR gene that conferred T3-independent transcriptional activation. Because thyroid hormone receptor controls HR expression in the central nervous system, whereas VDR functions in concert with the HR corepressor specifically in skin, a model is proposed wherein unliganded VDR upregulates the expression of HR, the gene product of which acts as a downstream comodulator to feedback repress DkkL1 and SOSTDC1, resulting in integration of BMP and Wnt signaling to drive the mammalian hair cycle and/or influencing epidermal function.

Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism

“…Substitutions in purines are commonly associated with activation and substitutions in pyrimidines are repressing. The activating or repressing VDREs for TPH1, TPH2, OXT, OXTR, AVPR1A , and AVPR1B are shown with base substitutions underscored (40, 80–81, 83, 157).…”

Hairless regulates p53 target genes to exert tumor suppressive functions in glioblastoma

“…As HR is likely epigenetically silenced during transformation given its infrequent rate of mutation in cancers, modalities that restore or inflate HR expression, such as through histone deacetylase inhibitors or demethylating agents, may be effective therapeutic strategies for this treatment refractory cancer. Of note, vitamin D can induce HR expression in keratinocytes, but it is unknown if this transcriptional program is intact in GBM . Nonetheless, vitamin D has been shown to antagonize GBM growth in vitro and in vivo, and VDR protein expression has been demonstrated to be a prognostic factor in GBM .…”

Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

“…57 As an example, the nuclear transcription factor coded for by the hairless gene, a key regulator of HF development and cycling that also exerts tumor suppression activity, [58][59][60] acts as an important TR repressor, presumably by recruiting histone deacetylases. 61 On the other hand, TR-mediated signalling suppresses HR expression in the CNS, 62 but it is as yet unclear whether this also occurs in human skin. TH thus has heterogeneous, cell-context dependent effects as inducer of either cell proliferation or differentiation, dependent on signalling context and cell type.…”